OHSU scientists find gene influencing drug withdrawal

PORTLAND, Ore. -- One of the genes that influences drug physical dependence and associated withdrawal has been identified at Oregon Health & Science University.

The gene, Mpdz, is involved in physical dependence on a class of drugs known as sedative-hypnotics, which are widely used for their euphoric and sedative effects. Drugs in this class include alcohol, inhalants, barbiturates, benzodiazepines, like Rohypnol or "roofies," and some other "club drugs."

Scientists in the Portland Alcohol Research Center (PARC) and the Department of Behavioral Neuroscience, OHSU School of Medicine, found Mpdz using mice bred to possess a region of a chromosome known to be associated with a predisposition to physical dependence and withdrawal from sedative-hypnotics like alcohol and barbiturates. During the four-year search, the scientists narrowed the initial field of more than 1,000 candidate genes to only five genes, and finally to one.

"We know that a host of biological and environmental factors interact in a complex manner throughout the addictive process to influence drug use or abuse. We think that physical dependence on sedative-hypnotic drugs and associated withdrawal episodes constitutes a motivational force that perpetuates drug use or abuse and contributes to relapse," said Nikki Walter, research associate in behavioral neuroscience and a study co-author.

"Now that we have identified one of the key genes, we can begin to study how this gene regulates brain circuits involved in drug dependence and withdrawal," said Kari Buck, Ph.D., associate professor of behavioral neuroscience and senior author of the study, which appears in the current issue of the journal Nature Neuroscience.

The discovery also is more evidence that drug and alcohol dependency is genetically determined. Previous OHSU studies have shown that genetics greatly influence alcohol and drug addiction and withdrawal.

"There are a lot of reasons why people drink or use other drugs and a variety of reasons why they lose control," Buck said. "For some of those people, it may be that they're seeking the high of alcohol and drugs like it, while some people might be seeking a mental escape from their current situation. This report focused on withdrawal because it can motivate a person to continue drug use and abuse, and contribute to the downward spiral of addiction."

The study focused on a chromosomal region previously shown to affect both alcohol and barbiturate dependence and withdrawal. Using inbred mouse strains that differ in drug withdrawal severity, the researchers developed recombinant mice to narrow the region of mouse chromosome 4 that accounted for the withdrawal phenotype to an interval containing only five genes.

"So for the five genes we found were expressed, we tested them for variations between strains that differ in drug withdrawal severity. These can be differences among individuals at the sequence level and/or at the level of expression - how much of the protein they have in their brain," said Renee Shirley, Ph.D., research associate in behavioral neuroscience and a study co-author.

"Out of the five candidate genes, only one, Mpdz, had nucleotide differences that changed amino acid sequence. Similarly, Mpdz was the only one that differed in its expression," she added. "Its expression also correlated with the severity of withdrawal among a panel of inbred mouse strains, which provided further support that this gene is a drug withdrawal gene."

Mpdz's protein product interacts with serotonin receptors in nerve cells in the brain. Serotonin receptors have been implicated in alcohol and drug addiction, as well as some psychiatric disorders. The human form of the Mpdz gene also interacts with serotonin receptors. "We know that there are different versions of the human Mpdz gene, but we don't yet know if these differences are functionally relevant at the protein level or at the level of behavior," Buck said.

To determine susceptibility to withdrawal in mice, researchers measured the severity of convulsions using a well-established behavioral test. They found that the greater the expression of Mpdz, the less susceptible the mice were to drug withdrawal seizures.

However, Mpdz does not regulate seizure susceptibility in general because its status is genetically correlated with seizures induced by some, but not all, drugs. "There are a lot of questions to pursue with this gene, a lot of questions we can now begin to answer," Shirley said.

As Mpdz's protein interactions, neural circuits, withdrawal-regulating mechanisms, and contribution to continued drug abuse and relapse are uncovered, new pharmaceutical therapies could be identified, Buck said. "For those people who are susceptible to drug withdrawal and are being treated for drug abuse, therapies focused on this gene and/or proteins it interacts with could make sense."

Buck added: "It's very possible that by increasing our understanding of how Mpdz acts in the brain, we can begin to develop alternative and/or complementary drug therapies and interventions for individuals."

Other study collaborators were: Matthew Reilly, Ph.D., PARC, the Department of Behavioral Neuroscience, OHSU School of Medicine; and Christoph Fehr, M.D., Department of Psychiatry, University of Mainz, Germany. The study was supported by the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, the National Institutes of Health.

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